CONFIDENTIAL Project Summary/Abstract This application is being submitted in response to an NIMH program announcement for Pharmacological Agents and Drugs for Mental Disorders. The goal of the proposal is to overcome the major hurdles that have impeded the discovery of new and improved antidepressant medications by combining state of the art automated behavioral assay technology with a novel and specialized approach to the discovery of drugs for the treatment of depression. Despite wide use and commercial success, current antidepressants have several deficiencies including poor efficacy and delayed onset of action. Progress in antidepressant drug discovery has been delayed severely by the lack of reliable, high throughput behavioral assays sensitive to the chronic effects of these drugs. We propose to develop SmartCube(r), PsychoGenics' automated, high-throughput behavioral testing system, to screen antidepressants for rapid onset of activity. In Phase I, we will develop a methodology to screen for fast acting antidepressants. To accomplish this, we will first establish the time course and onset of action of the chronic antidepressant signature in SmartCube(r). The time required for the chronic signatures to reach a steady state will be determined for a small set of prototypical antidepressants (fluoxetine, venlafaxine and imipramine). The onset of the chronic signature will be determined for these antidepressants by establishing the earliest time at which the antidepressant signature more closely resembles the chronic rather than acute signature. We will then utilize this information to establish a reference database of chronic antidepressant signatures in SmartCube(r). This reference database will be used to screen novel compounds for fast onset antidepressant activity. Up to 100 compounds that have previously shown activity in our acute antidepressant SmartCube(r) screen will be tested for fast onset activity. The libraries that we have previously screened were comprised of a diverse mix of known and novel, target- specific, target-nonspecific and target-undetermined small molecules. Compounds that show a high probability of showing a chronic antidepressant signature will be considered "preliminary hits". These compounds will be confirmed in tests of chronic antidepressant efficacy that test for onset of action. Compounds that show rapid onset activity in at least one of these tests will be considered "validated hits". In Phase II of the proposal, 3-5 validated hits will be advanced and the metabolic, pharmacokinetic and safety studies required to file an IND for at lead one "optimized lead" will be completed. We believe that this approach will result in the discovery of novel, faster acting antidepressants. CONFIDENTIAL Project Narrative Major depression represents a major unmet medical need, but the number of new medications introduced to the market in recent years has been steadily declining. The traditional molecular target driven approached to drug discovery for antidepressants have had limited success due to the complexity and lack of understanding regarding the molecular basis of the disorder. The behavior-based approach described in this proposal provides an exciting new alternative with the potential to more efficiently identify novel, more efficacious antidepressants with a faster onset of action. [unreadable] [unreadable] [unreadable]